Advertisement

Dynamics of Platelet Functional Recovery Following a Clopidogrel Loading Dose in Healthy Volunteers

      A clopidogrel loading dose before percutaneous coronary intervention may reduce ischemic events but can increase bleeding risk and result in delayed treatment in patients who subsequently require surgical revascularization. The goal of this study was to examine the dynamics of platelet functional recovery after the common clinical scenario of a single 600-mg loading dose of clopidogrel. Fourteen volunteers were administered clopidogrel 600 mg. Platelet reactivity was measured before exposure, 4 hours after exposure, and then daily for 8 days using the VerifyNow P2Y12 assay. Percentage inhibition (PI) was calculated as the relative change in P2Y12 reaction units from baseline. One day after clopidogrel, the median PI was 39.9% (range 8.5% to 97.7%). Before day 5, the number of days after exposure was significantly but weakly correlated with PI (Pearson's coefficient = 0.45, R2 = 0.20, p = 0.001), while most of the variance in PI on each day of recovery was explained by the PI that was observed the previous day (Pearson's coefficient = 0.95, R2 = 0.92, p <0.001). The decay in PI over time was exponential, with a common ratio of 17% relative reduction per day (95% confidence interval 10% to 23%). Similar findings were observed when the effect of clopidogrel was defined by residual platelet reactivity or by the adenosine diphosphate–prostaglandin E1/iso–thrombin receptor–activating peptide ratio. In conclusion, platelet inhibition on each day after a loading dose varies considerably among subjects. The level of inhibition depends less on the number of days after exposure than on the magnitude of initial inhibition after loading. A strategy of individual platelet function monitoring should be examined in patients requiring cardiac surgery after clopidogrel loading.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Smith C.S.
        ACC/AHA/SCAI guideline update for percutaneous coronary intervention.
        Circulation. 2006; 113: 156-175
        • Hochholzer W.
        • Trenk D.
        • Frundi D.
        • Blanke P.
        • Fischer B.
        • Andris K.
        • Bestehorn H.P.
        • Buttner H.J.
        • Neumann F.J.
        Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention.
        Circulation. 2005; 111: 2560-2564
        • Kandzari D.E.
        • Berger P.B.
        • Kastrati A.
        • Steinhubl S.R.
        • Mehilli J.
        • Dotzer F.
        • Ten Berg J.M.
        • Neumann F.J.
        • Bollwein H.
        • Dirschinger J.
        • Schomig A.
        Influence of treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization.
        J Am Coll Cardiol. 2004; 44: 2133-2136
        • Steinhubl S.R.
        • Berger P.B.
        • Mann III, J.T.
        • Fry E.T.
        • DeLago A.
        • Wilmer C.
        • Topol E.J.
        Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
        JAMA. 2002; 288: 2411-2420
        • Kapetanakis E.I.
        • Medlam D.A.
        • Boyce S.W.
        • Haile E.
        • Hill P.C.
        • Dullum M.K.
        • Bafi A.S.
        • Petro K.R.
        • Corso P.J.
        Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache?.
        Eur Heart J. 2005; 26: 576-583
        • Leong J.Y.
        • Baker R.A.
        • Shah P.J.
        • Cherian V.K.
        • Knight J.L.
        Clopidogrel and bleeding after coronary artery bypass graft surgery.
        Ann Thorac Surg. 2005; 80: 928-933
        • Chen L.
        • Bracey A.W.
        • Radovancevic R.
        • Cooper Jr, J.R.
        • Collard C.D.
        • Vaughn W.K.
        • Nussmeier N.A.
        Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting.
        J Thorac Cardiovasc Surg. 2004; 128: 425-431
        • Braunwald E.
        • Antman E.M.
        • Beasley J.W.
        • Califf R.M.
        • Cheitlin M.D.
        • Hochman J.S.
        • Jones R.H.
        • Kereiakes D.
        • Kupersmith J.
        • Levin T.N.
        • et al.
        ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina).
        Circulation. 2002; 106: 1893-1900
        • Gurbel P.A.
        • Bliden K.P.
        • Hiatt B.L.
        • O'Connor C.M.
        Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.
        Circulation. 2003; 107: 2908-2913
        • Angiolillo D.J.
        • Fernandez-Ortiz A.
        • Bernardo E.
        • Ramirez C.
        • Sabate M.
        • Banuelos C.
        • Hernandez-Antolin R.
        • Escaned J.
        • Moreno R.
        • Alfonso F.
        • Macaya C.
        High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability.
        Eur Heart J. 2004; 25: 1903-1910
        • Lepantalo A.
        • Virtanen K.S.
        • Heikkila J.
        • Wartiovaara U.
        • Lassila R.
        Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions.
        Eur Heart J. 2004; 25: 476-483
        • Malinin A.
        • Pokov A.
        • Spergling M.
        • Defranco A.
        • Schwartz K.
        • Schwartz D.
        • Mahmud E.
        • Atar D.
        • Serebruany V.
        Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12® rapid analyzer: the Verify Thrombosis Risk Assessment (VERITAS) study.
        Thromb Res. 2007; 119: 277-284
        • Paniccia R.
        • Antonucci E.
        • Gori A.M.
        • Marcucci R.
        • Giglioli C.
        • Antoniucci D.
        • Gensini G.F.
        • Abbate R.
        • Prisco D.
        Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients.
        J Thromb Haemost. 2007; 5: 1839-1847
        • van Werkum J.W.
        • van der Stelt C.A.
        • Seesing T.H.
        • Hackeng C.M.
        • ten Berg J.M.
        A head-to-head comparison between the VerifyNow P2Y12 assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective percutaneous coronary intervention.
        J Thromb Haemost. 2006; 4: 2516-2518
        • Malinin A.
        • Pokov A.
        • Swaim L.
        • Kotob M.
        • Serebruany V.
        Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel.
        Methods Find Exp Clin Pharmacol. 2006; 28: 315-322
        • Price M.J.
        • Coleman J.L.
        • Steinhubl S.R.
        • Wong G.B.
        • Cannon C.P.
        • Teirstein P.S.
        Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers.
        Am J Cardiol. 2006; 98: 681-684
        • von Beckerath N.
        • Taubert D.
        • Pogatsa-Murray G.
        • Schomig E.
        • Kastrati A.
        • Schomig A.
        Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) trial.
        Circulation. 2005; 112: 2946-2950
        • Muller I.
        • Seyfarth M.
        • Rudiger S.
        • Wolf B.
        • Pogatsa-Murray G.
        • Schomig A.
        • Gawaz M.
        Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement.
        Heart. 2001; 85: 92-93
        • Weber A.A.
        • Braun M.
        • Hohlfeld T.
        • Schwippert B.
        • Tschope D.
        • Schror K.
        Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers.
        Br J Clin Pharmacol. 2001; 52: 333-336
        • George J.N.
        Platelets.
        Lancet. 2000; 355: 1531-1539